Targeted drug delivery systems aim to improve efficacy and reduce toxicity of potent therapeutics in treatment of a variety of diseases. For example, chemotherapy is one of the major treatments for cancers but is linked with life-threatening side effects because of its toxicity on healthy proliferating cells and relation to multi-drug resistance against anticancer drugs. Tumor-targeting delivery systems have been developed to alter the biodistribution of drugs, aiming to achieve drug accumulation in cancer tissue through enhanced permeability and retention (EPR) effect and/or specific cell surface recognition.
On the other hand, controlled drug release at pathological tissues is desired to maintain the expected therapeutic properties of any delivered potent agent. Conventional delivery systems for anti-cancer drugs utilize biodegradation of materials that encapsulate the drugs, either time-dependent manner or through environmentally triggered mechanisms. For example, the extracellular pH in tumor tissue is slightly lower than that in the normal tissue, which has been used to develop acidity-triggered drug release at tumor tissue. (See, e.g., Lee, E. S.; Gao, Z.; Bae, Y. H. J Control Release 2008, 132, 164.) In addition, the significantly increased acidity in endosomes and lysosomes in cells also enables the use of low pH-initiated release of drugs from endocysed drug carriers as a complementing approach to increase the interacting efficacy of drugs with their intracellular targets. (Torchilin, V. P.; Lukyanov, A. N. Drug Discov Today 2003, 8, 259-266.)
Boronic acids are capable of forming covalent linkages with 1,2-, or 1,3-dihydroxyl (diol) structures to give boronate esters. Dissociation constants of boronate esters in aqueous solutions have been reported in the micromolar range, (Lorand, J. P.; Edwards, J. O. The Journal of Organic Chemistry 1959, 24, 769) and the stabilities of these esters are dependent upon factors such as pH and buffer formulation. In particular, the covalent association between boronic acid and diol moieties gives stable boronate conjugates in aqueous solutions at neutral and basic pH, while acidic pH triggers dissociation of boronate esters to release free boronic acid from the diol. This dynamic association-dissociation process has been systematically studied from the perspective of boronic acid and diol structure, as well as influence from pH buffer formulation. (See, Springsteen, G.; Wang, B. H. Tetrahedron 2002, 58, 5291; and Yan, J.; Springsteen, G.; Deeter, S.; Wang, B. H. Tetrahedron 2004, 60, 11205.) Boronate ester formation and related mechanisms have also been utilized to develop sensors for carbohydrates and amino acids and selective transporters of nucleosides, saccharides, and nucleotides. (See, e.g., James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Nature 1995, 374, 345; James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Angewandte Chemie-International Edition 1996, 35, 1910; James, T. D.; Sandanayake, K. R. A. S.; Iguchi, R.; Shinkai, S. Journal of the American Chemical Society 1995, 117, 8982; Mohler, L. K.; Czarnik, A. W. Journal of the American Chemical Society 1993, 115, 7037; Riggs, J. A.; Hossler, K. A.; Smith, B. D.; Karpa, M. J.; Griffin, G.; Duggan, P. J. Tetrahedron Letters 1996, 37, 6303; Mohler, L. K.; Czarnik, A. W. Journal of the American Chemical Society 1993, 115, 2998; and Paugam, M.-F.; Bien, J. T.; Smith, B. D.; Chrisstoffels, L. A. J.; de Jong, F.; Reinhoudt, D. N. Journal of the American Chemical Society 1996, 118, 9820.) It has also been applied in development of medical devices, for example, as part of strategies to construct anti-fouling hydrogel coating and to crosslink polymer hydrogel networks which can go through pH-sensitive sol-gel transition with potential use in targeted drug delivery to GI tract. (See, Winblade, N. D.; Schmokel, H.; Baumann, M.; Hoffman, A. S.; Hubbell, J. A. J. Biomed. Mater. Res. 2002, 59, 618; and Roberts, M. C.; Hanson, M. C.; Massey, A. P.; Karren, E. A.; Kiser, P. F. Adv Mater 2007, 19, 2503.)
While boronic acid moieties are common among many therapeutics, effective delivery can be problematic, especially from one compound to another. There remains an on-going concern in the art to develop a general drug delivery system for targeted therapy of cancer and other disease states, so as to better utilize the benefits and advantages of such boronic acid therapeutics.